Association between recently raised anticholinergic burden and risk of acute cardiovascular events: nationwide case-case-time-control study

Abstract Objective To evaluate the association between recently raised anticholinergic burden and risk of acute cardiovascular events in older adults. Design Case-case-time-control study (ie, incorporating a case crossover design and a control crossover design consisting of future cases). Setting Taiwan’s National Health Insurance Research Database. Participants 317 446 adults aged ≥65 who were admitted to hospital because of an incident acute cardiovascular event between 2011 and 2018. Acute cardiovascular events included myocardial infarction, strokes, arrhythmias, conduction disorders, and cardiovascular death. Main outcome measures The anticholinergic burden was measured for each participant by adding up the anticholinergic scores for individual drugs using the Anticholinergic Cognitive Burden Scale. Scores were classified into three levels (0 points, 1-2 points, and ≥3 points). For each participant, anticholinergic burden levels during hazard periods (day −1 to −30 before the cardiovascular event) were compared with randomly selected 30 day reference periods (ie, periods between days −61 and −180). Conditional logistic regression determined odds ratios with 95% confidence intervals to evaluate the association between acute cardiovascular events and recently raised anticholinergic burden. Results The crossover analyses included 248 579 current cases. Participants’ average age on the index date was 78.4 years (standard deviation 0.01), and 53.4% were men. The most frequently prescribed drugs with anticholinergic activity were antihistamines (68.9%), gastrointestinal antispasmodics (40.9%), and diuretics (33.8%). Among patients with varying levels of anticholinergic burden in different periods, more patients carried higher levels of anticholinergic burden during hazard periods than during reference periods. For example, 17 603 current cases had 1-2 points of anticholinergic burden in the hazard period with 0 points in the reference period, while 8507 current cases had 0 points in the hazard period and 1-2 points in the reference period. In the comparison of 1-2 points versus 0 points of anticholinergic burden, the odds ratio was 1.86 (95% confidence interval 1.83 to 1.90) in the case crossover analysis and 1.35 (1.33 to 1.38) in the control crossover analysis, which yielded a case-case-time-control odds ratio of 1.38 (1.34 to 1.42). Similar results were found in the comparison of ≥3 versus 0 points (2.03, 1.98 to 2.09) and ≥3 versus 1-2 points (1.48, 1.44 to 1.52). The findings remained consistent throughout a series of sensitivity analyses (eg, cut-off points for anticholinergic burden categories were redefined and different scales were used to measure anticholinergic burden). Conclusions An association was found between recently raised anticholinergic burden and increased risk of acute cardiovascular events. Furthermore, a greater increase in anticholinergic burden was associated with a higher risk of acute cardiovascular events.


log (
Pr(Y = 1|X) 1 − Pr(Y = 1|X) ) = β 0 + β 1 X + ⋯ , Pr(Y = 1|X) The odds ratio between Y and X :   = exp(β 1 ) The (1 − α)% two − sided confidence interval for β 1 ∶ β̂1 ±  1− ∝ 2  β̂1 ,  β̂1 as standard error of β̂1 The (1 − α)% two − sided confidence interval for   ∶ (  ,   ) = exp (β̂1 ±  Both the case-time-control (CTC) and the case-case-time-control (CCTC) designs assume that the observed odds ratio among cases is the product of the odds ratio for the causal effect of the exposure on outcome multiplied by the odds ratio for exposure trends over calendar time: OR case = OR causal × OR time-trend By contrast, the odds ratio among the controls can only be explained by exposure trends without specific causality: To obtain the odds ratio for the causality of exposure on outcome (OR causal ), the cases' odds ratio (OR causal × OR time-trend ) is divided by the corresponding odds ratio of concurrent matched controls (OR time-trend ).
The main difference between the two control analyses is that the CCTC design uses future cases as the control group, whereas the CTC design employs external non-case controls in which the events did not occur.The CCTC design assumes that the trend in exposure over calendar time is the same for current and future cases because both of them experience the events (1).If there is an issue of protopathic bias from the medications used for the prodromes of the events, the exposure time trends will be observed in both groups.This allows the reference time periods sampled from future cases in CCTC analysis to provide a better estimate of the time effect, when compared to the periods sampled from external non-case controls in the CTC design.The figures illustrate the concepts in the case-timecontrol and case-case-time-control design and how the future case methods can address the protopathic bias under discussion.401-405, 410-414, 415-417, 426-428, 430-437, 440-441, 443 .Other GI agents

Genitourinary antispasmodics
*A dot (.) in the table means the medication is not scored/listed in the scale.Medications with no scoring in the scales were calculated as 0 point in our study.†Multiple combination drugs sharing the same ATC codes; only the ingredients with anticholinergic activity listed ‡Combination drugs with redefined score: The score of a combination drug was redefined as the score of the ingredient with the highest score in the combination drug.
Supplementary table 3. Definition of anticholinergic burden categories for anticholinergic burden in the hazard and reference period.

Anticholinergic burden category
Total anticholinergic burden Used for analyses Hazard period Reference period* Provide no information *One randomly selected from four reference periods †For instance, participants with 1-2 points in hazard and 0 point in reference period were grouped into category A, and those with 0 points in hazard and 1-2 point in reference period were category B. The categories with opposite burden, such as category A and B, were defined as corresponding burden categories for the crossover analysis.

Supplementary
In CCTC analysis, we have   and   , here we use   (  ,   ) and   (  ,   )

table 4 . Comorbidities collected for baseline characteristics and used for disease risk score matching.
Supplementary table 5.

Supplementary table 7. Different scales for anticholinergic burden measurement in sensitivity analysis.
Medications with none or limited anticholinergic activity (= 0 point) were not published in the scale or article.†The number of medications determined to have anticholinergic activity in any potency level (low to high anticholinergic pote ncy, score > 0 point).The medications recognised to be "none or limited anticholinergic activity (= 0 point)" were not included in the number of drugs scored in this table.